The Institute of Medicine recently listed atrial fibrillation (AF) as its top priority. AF is the most common heart rhythm disorder, afflicting 5 million Americans, in whom it may cause symptoms from irregular heartbeats, stroke, heart failure, and even death. Unfortunately, AF therapy remains limited. Therapy with anti- arrhythmic drugs is poorly tolerated, has frequent side effects and does not reduce complications since AF is not cured. Ablation is a minimally invasive therapy that has attracted considerable recent attention, because it may potentially eliminate AF. Unfortunately, ablation is not widely adopted because it is technically difficult, lengthy (4+ hours), has only <60 % success (compared to >90% for most other arrhythmias), and a 5-10% risk of serious complications. A major cause of these limitations is that AF on the ECG represents many different rhythm disorders (arrhythmia mechanisms), that currently cannot be diagnosed in each patient. As a result, AF ablation cannot be directed to them, and is empiric with extensive destruction of the atrium. Our products represent a disruptive technology that will dramatically improve and simplify AF ablation, rapidly widening its adoption. Our products quickly and accurately diagnose the causal arrhythmias for AF in each individual. Once identified, ablation can be targeted directly at these AF sources for cure. We have substantial preliminary data to support this paradigm. Our AFSourceTM product has for the first time diagnosed localized electrical rotors or repetitive focal beats as the AF mechanism in 42/53 AF patients. Patients in whom these mechanisms were ablated had significantly higher freedom from AF than those in whom ablation did not bisect these sites (92% vs 62% at 2 years, p<0.001). Prospectively, ablation at these sites (known as Focal Impulse and Rotor Modulation therapy, or FIRM) was able to terminate AF in as little as 5.5 minutes (vs. hours for conventional ablation). This project will finalize our technology for commercialization. Proposed studies address 3 Aims: 1) To perform mechanistic studies to diagnose rotors/focal beats and identify those that are primary sources for AF;2) To perform a pilot clinical study comparing direct ablation at AF arrhythmia mechanisms diagnosed by AFSourceTM (FIRM therapy) to conventional ablation;and 3) To prepare a formal report for Phase II SBIR and FDA applications. Successful completion of our Aims will, scientifically, demonstrate for the first time that rotors and focal beats sustain human AF and, clinically, define a treatment paradigm for rapid simple AF cure. Our product and FIRM treatment may cause a paradigm-shift in the standard of care for AF. By improving and simplifying AF ablation, procedures will be shortened and better tolerated, with potentially fewer complications, better facility and personnel utilization, and lower overall costs. These factors are likely to widen adoption, enabling more patients to access curative therapy for AF. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is an enormous public health problem that affects 5 million Americans, causing morbidity or death from stroke, rapid heartbeats and heart failure. This phase I SBIR sets out to prove that small regions of the heart detected by inventions directly cause AF, and that physicians can modify these regions for a rapid and simple cure. This high impact project will result in a paradigm-shift in AF therapy.